Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkβ

M Yuan, N Konstantopoulos, J Lee, L Hansen, ZW Li… - Science, 2001 - science.org
M Yuan, N Konstantopoulos, J Lee, L Hansen, ZW Li, M Karin, SE Shoelson
Science, 2001science.org
We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and
dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression
of the IκB kinase β (IKKβ) attenuated insulin signaling in cultured cells, whereas IKKβ
inhibition reversed insulin resistance. Thus, IKKβ, rather than the cyclooxygenases, appears
to be the relevant molecular target. Heterozygous deletion (Ikkβ+/−) protected against the
development of insulin resistance during high-fat feeding and in obese Lepob/ob mice …
We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IκB kinase β (IKKβ) attenuated insulin signaling in cultured cells, whereas IKKβ inhibition reversed insulin resistance. Thus, IKKβ, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkβ +/−) protected against the development of insulin resistance during high-fat feeding and in obese Lepob/ob mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKβ pathway as a target for insulin sensitization.
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